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A more carefully designed review of the evidence refutes the findings of a flawed analysis published earlier this year

by Craig Weatherby

The American Heart Association and many other authoritative institutions advise people to eat more fish and take fish oil supplements. And that guidance flows from the huge body of evidence indicating that the long-chain marine omega-3s in fish oil (EPA and DHA) reduce the risk of heart attacks, strokes, and sudden cardiac death.

This is not to suggest that marine omega-3s are miracle drugs, or that they are safe for everyone. For example, we’ve been quick to report the findings of several recent studies, which indicate that fish oil supplements may be unsafe for people who are so prone to deadly heart arrhythmias (erratic heart beats) that they need an implantable cardiac defibrillator (ICD) in their chest (see “Fish Oil Can't Rescue the Sickest Cardiac Patients' Heart Rhythms” ).

But informed scientists knew they were witnessing a serious misstep when, in March of 2006, the prestigious

British Medical Journal (BMJ) published the largely negative findings of a review of selected portions of the scientific evidence regarding omega-3s and the risk of heart problems (Hooper L 2006).

Key Points

A new evidence review finds strong evidence that the omega-3s in fish and fish oil help prevent cardiovascular disease and its consequences.

The authors of the new review avoided the fatal flaws in another recent evidence review, whose negative findings contradicted the scientific consensus that fish is good for the heart.

We need more randomized controlled clinical trials to answer remaining questions, but it is clear that fish offers real cardiovascular benefits.

That research paper—from a team led by Dr. Lee Hooper of the University of East Anglia in Britain—contradicted the indications from a vast body of research, as well as the positive findings of virtually all prior evidence reviews. It was no wonder that Dr. Hooper’s findings sparked a storm of protest from colleagues worldwide.

Worse, the Hooper study’s fatal flaws led to conclusions and headlines that may have weakened people’s well-founded expectations that consuming more fish and fish oil would help protect their heart health.

We can only hope that the news media will report the findings of the new evidence review, which affirm the ability of the marine omega-3s in fish oil (EPA and DHA) to reduce the risk of cardiovascular disease and its potentially crippling or deadly consequences.

The background to the positive new evidence reviewThe negative evidence review published by Dr. Hooper’s team earlier this year concluded that, when analyzed as a group, the studies they selected did not show clear evidence that omega-3s protect against cancer, strokes, or heart attacks.

As they said, “It is not clear that dietary or supplemental omega 3 fats alter total mortality, combined cardiovascular events or cancers in people with, or at high risk of, cardiovascular disease or in the general population.”

But as soon as the British researchers published these consensus-confounding conclusions, the “rapid responses” mailbox at the British Medical Journal (BMJ) was filled with a flood of letters from experts who found serious fault with the Hooper team’s methods. To read the responses sent to the BMJ, which echo our own critique, click here.

We published an immediate response to the Hooper review in Vital Choices, with the help of world-renowned fatty acid researcher William E. Lands, Ph.D. And it was gratifying to see that it anticipated the criticisms leveled by many leading researchers in the field (see “Experts Find New Fish-and-Health Review Deeply Distorting”).

If the existing evidence had led virtually every major public health institution to recommend fish for heart health, how could Dr. Hooper’s team have gotten it so wrong?

"[the new evidence review represents]... a large step forward in helping to resolve controversies related to the beneficial effects of [omega-3 fatty acids] on [cardiovascular disease]" - Richard Decklebaum, M.D. and Sharon Akabas, Ph.D. of Columbia University

The review by Dr. Hooper’s team excluded an enormous body of relevant, almost entirely positive, evidence derived from test tube, animal, and population studies. But that wasn’t the main problem, since the Hooper review was intended to judge the status of evidence from controlled human studies.

This was a legitimate approach, since only human studies—especially randomized controlled clinical trials (RCTs)—can confirm the cardiovascular benefits of omega-3 fatty acids from fish.

The experts who sent critical responses to the BMJ found the premises and study-selection criteria of the Hooper review sound, but almost all identified one or more of these four serious flaws:

The Hooper review gave undue weight to one flawed trial (Burr ML 2003). That study is the only one ever conducted in men with angina (chest pain caused by clogged arteries); researchers who wrote a 2004 evidence review for the U.S. government rated the Burr angina trial as “poor quality”. In fact, if not for the great weight given the anomalous findings of this one study, Dr. Hooper’s evidence review would have echoed the unambiguously positive findings of other recent evidence reviews (e.g., Bucher 2002, Wang 2004).

The Hooper review gave undue weight to small studies (in violation of the authors declared criteria).

Most of the studies in the Hooper review that found no benefit from omega-3s did not consider omega-6 intake, despite abundant evidence that people’s dietary omega-3/omega-6 ratio is critical to cardiovascular health.

The Hooper review included studies using omega-3 plant oils, despite abundant evidence that they are not nearly as effective as marine omega-3s when it comes to improving key aspects of cardiovascular health.

Cardiac experts compile a more careful analysisMany leading cardiac researchers commented that the headlines generated by the flawed conclusions of Dr. Hooper’s team could harm public health, by casting unjustified doubts on the heart benefits that omega-3s bring the vast majority of people.

Fortunately, the results of a new evidence review, published last week in the well-respected American Journal of Clinical Nutrition, and they reinforce the positive findings of the majority of prior reviews (excepting Dr. Hooper’s). The new review was led by Chenchen Wang, M.D., M.Sc.—an Assistant Professor of Medicine at the Tufts University School of Medicine—and it avoided the errors made by Dr. Hooper’s team.

Center or its Cardiovascular Nutrition Laboratory, near Boston. Accordingly, they possessed extraordinary expertise in the pitfalls of research into omega-3s and cardiovascular disease.

One notable exception to Dr. Wang’s Tufts-centered team was Professor William S. Harris, Ph.D. of Kansas City, who teaches and conducts research at the University of Missouri and at the Mid America Heart Institute at Saint Luke's Hospital.

Dr. Harris is a renowned heart researcher, and most of the 140-plus biomedical studies he’s led or co-authored relate to the role of fatty acids in heart disease. (We heard and spoke with Dr. Harris at last year’s Seafood & Health conference in Washington, D.C.)

Editorial praises quality of new evidence reviewRather than characterize the quality and significance of Dr. Wang’s new evidence review ourselves, we’ll quote some of the comments made by Richard Deckelbaum, M.D. and Sharon R. Akabas, Ph.D. of Columbia University, who penned the editorial that accompanied it. (Text in brackets is inserted for clarity, or indicates replacement of scientific terminology with lay language of identical meaning):

“In this issue of the Journal, Wang et al [Dr. Wang and his co-authors] take a large step forward in helping to resolve controversies related to the beneficial effects of [omega-3 fatty acids] on [cardiovascular disease] outcomes. .. In total, the evidence indicates that increased consumption of the [omega-3 fatty acids] EPA and DHA, either through fish or supplements or both, reduced the rates of all-cause mortality, myocardial infarction, and sudden cardiac death."

Drs. Deckelbaum and Akabas also praised the methodology used by Dr. Wang and his colleagues. The underlined text highlights two other superior aspects of the new evidence review, in addition to its avoidance of the problems so many experts registered in their responses to the Hooper review:

“… the authors have written a formidable review of this ‘basket’ of [omega-3 fatty acid] trials and have been able to classify them into different groups according to how [omega-3 fatty acid] intake is linked to specific endpoints relating to CVD and also by differentiating between secondary- and primary-

“Because Wang et al [the authors of the new review] measured the effect of [omega-3 fatty acids] on actual CVD endpoints, they included only randomized controlled trials and prospective cohort studies that monitored patients for [more than one year], and, in the case of the case-control studies, only those that actually documented intakes of fish oil and [omega-3 fatty acids]."

This last point is critical, since, as we’ve heard leading fatty acid researchers Joseph Hibbeln M.D. and William Lands, Ph.D. say, “the tissue is the issue”, meaning that study results have far more meaning when you determine the actual levels of omega-3s in people’s bodies—the best measure of omega-3 intake—instead of the usual method of relying on estimates based on eating diaries or after-the-fact surveys.

In their editorial, Drs. Deckelbaum and Akabas also noted that the new review reinforces the general safety of marine omega-3s: “They reviewed many more studies for potential adverse effects of [omega-3 fatty acids]; of particular importance is that no or very few complications were documented.”

(As we’ve said, recent studies indicate that omega-3 supplements may be unsafe for patients with implanted cardiac defibrillators, and they may be contraindicated for some people who are taking blood-thinning drugs.)

The new review’s specific findingsIt’s worth quoting directly from the conclusions of the new review by Dr. Wang’s team, because they confirm the conclusions of all prior reviews—other than Dr. Hooper’s—and flowed from findings based on superior study-selection criteria and analytical approaches:

“Primary prevention of cardiovascular disease was reported in 1 RCT, in 25 prospective cohort studies, and in 7 case-control studies. No significant effect on overall deaths was reported in 3 RCTs that evaluated the effects of fish oil in patients with implantable cardioverter defibrillators.”

“Most cohort studies reported that fish consumption was associated with lower rates of all-cause mortality and adverse cardiac outcomes. The effects on stroke were inconsistent.”

“Evidence suggests that increased consumption of [omega-3 fatty acids] from fish or fish-oil supplements, but not of [omega-3] -linolenic acid [from plants], reduces the rates of all-cause mortality, cardiac and sudden death, and possibly stroke.”

“The evidence for the benefits of fish oil is stronger in secondary- than in primary-prevention settings. Adverse effects appear to be minor."

Questions remain, but review confirms heart benefits of omega-3sEven though it is clearly superior to the Hooper review—which drew unwarranted conclusions and prompted headlines damaging to public health—the new evidence analysis by Dr. Wang’s team cannot settle all of the remaining questions.

Drs. Akabas and Deckelbaum identified five of these lingering areas of uncertainty. (Again, the text in brackets is inserted for clarity, or indicates replacement of scientific terminology with lay language of identical meaning):

“Will the effects of long-chain [omega-3 fatty acids] be enhanced by a concomitant reduction in [omega-6 fatty acids]? A recent analysis by Hibbeln et al strongly supports this possibility. Although some attention has been focused on the ratios of [omega-3 to omega-6 fatty acids], we suggest that the total amount of each type of [fatty acid] also demands consideration.”

“What are the dose-response effects of EPA and DHA, and are tissue concentrations of these [omega-3 fatty acids] critical to achieving biological effects? Which tissues need to be measured as the best surrogates for CVD outcomes? In most reported studies, plasma or tissue concentrations of [omega-3 fatty acids] are not measured, and the use of these as surrogates has not necessarily been validated.”

“What are the basic molecular mechanisms underlying the wide array of effects of these potent CVD modulators? Arecent study suggests that a metabolite of EPA is responsible for some biological effects [Arita M 2006]. Through the identification of active [omega-3 fatty acid] metabolites [i.e., breakdown products] and their downstream pathways, underlying mechanisms will be better elucidated.”

“Is DHA equally as effective as or more effective than EPA in reducing CVD endpoints, or is a combination of both required? A recent review [Mori TA 2006] suggests that, for many endpoints relating to CVD, DHA is equally as effective as or more so than EPA. Although improved CVD outcomes have been achieved by intakes of a combination of these 2 [omega-3 fatty acids] in various ratios, “optimal” ratios are still to be determined.”

“Does an increase in the ratio of EPA to DHA reduce CVD equally in populations with high baseline intakes of EPA and DHA and in populations with low intakes? The analysis by Wang et al [i.e., the new evidence review] suggests that intervention trials show less CVD protection in some studies from Norway, Finland, and Japan—countries with high fish intakes."

The conclusions drawn by Drs. Deckelbaum and Akabas serve to underscore the validity of current recommendations that Americans need to eat more fish. And as the following underlined passage from their editorial makes clear, fears about mercury and PCBs can be addressed by picking the right fish:

“Despite concern about toxins in fish, proper selection and preparation of fish results in a low risk from toxins, especially when compared with low intakes of EPA and DHA.”

“What should we recommend today? We believe thatthe body of existing evidence is strong enough to suggest that in the United States, certainly, and in other countries where [omega-3 fatty acid] consumption is low, public health initiatives are needed to increase intakes of EPA and DHA.”

Drs. Akabas and Deckelbaum also said that they believe the new findings support the current recommendations of leading health authorities, which they detailed:

“With all the limitations in mind, and given the little to no risk associated with their consumption, the American Heart Association and several international health agencies recommend intakes of [about 1 gram of EPA+DHA per day] for patients with known CVD [cardiovascular disease] and of [400–500 mg of EPA+DHA per day (about 2 servings of oily fish per week)] for those without CVD."

As far as concerns about contaminants, test data from government and private studies shows that the purest, safest species include our own selections: wild Alaskan salmon (all types), halibut, sablefish, sardines, and scallops, and small (hence, low-mercury) tuna.